PROJECT SUMMARY The goal of this 3-year R01 proposal is to study the long-term effects of antidepressant medications on offspring mental health. Fetal exposure to antidepressants remains an important public health question, because the use of these medications by pregnant women is increasing. We will focus on a particular class of antidepressants, selective serotonin reuptake inhibitors (SSRIs), which when taken by pregnant mothers, cross the placenta and enter fetal circulation. Most studies have only followed offspring through early childhood. We previously showed in both animal studies that offspring exposed to SSRIs had higher rates of depression in adolescence. However, the follow-up ended at age 14, an age when offspring are only beginning to enter the period of risk. Furthermore, maternal depression, which could be an important confounder, was only known for mothers who were treated by specialists, and therefore had more severe depression. To address gaps, we have now designed a proposal that includes three cohorts across two continents: The first (cohort 1), is based on Danish National Register data, a population-wide system of birth, medical, and prescription records that will allow us to both validate our previous findings in an independent population, and extend the window of observation out through adolescence and early adulthood (N~840,000). The second (cohort 2) is a Danish National Birth cohort that is nested within the first cohort but that includes mothers with a wider range of clinical and sub-clinical depression (N=100,417). The third cohort (cohort 3) is based on the Mayo Clinic?s Rochester Epidemiology Project, a system of electronic health records that will allow us to test findings in a U.S. population with detailed clinical characterization across all levels of care (N=26,770). Each cohort will be designed to include offspring born 1997 onwards; thus, oldest offspring will be age 24 by the end of the study. We will use the cohorts to test whether in utero SSRI exposure increases risk for depressive disorders in adolescence and early adulthood in each of the three cohorts, and whether the findings are specific to depressive disorders or reflect more general developmental problems. We will also test whether findings vary by sex of offspring or trimester of exposure. This proposal brings together three cohorts across continents to test findings in adolescence, and extend window of observation into early adulthood. In the process, we will have the longest follow-up of any SSRI exposure study. If we find incremental risks of SSRI exposure, this can inform clinical practice, where other pharmacological and psychotherapeutic alternatives may be able to better protect mothers and offspring. Conversely, if we find no risks, results will support safe and rational use of these medications, and potentially increase compliance.